Oxidative intramolecular coupling of 2,3-disubstituted phenyl acrylic acids and derivatives promoted by di-tert-butylperoxide

Article abstract of DOI:10.1016/j.cclet.2013.11.004

Polymethoxy-substituted phenanthrene-9-carboxylic acids or their methylate are key intermediates for the synthesis of tylophora alkaloids and their analogs. An intramolecular oxidative coupling reaction of unfunctionalized 2,3-disubstituted phenyl acrylic

Full text of DOI:10.1016/j.cclet.2013.11.004

Chinese Chemical Letters 25 (2014) 348–350
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Oxidative intramolecular coupling of 2,3-disubstituted phenyl acrylic
acids and derivatives promoted by di-tert-butylperoxide
De-Rong Ji, Hua Yang, Xiao-Jing Zhao, Hao Yang, Yang-Zhao Liu, Dai-Hui Liao,
*
Chun Feng, Cheng-Gang Zhang
College of Chemistry and Materials, Sichuan Normal University, Chengdu 610066, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Polymethoxy-substituted phenanthrene-9-carboxylic acids or their methylate are key intermediates for
the synthesis of tylophora alkaloids and their analogs. An intramolecular oxidative coupling reaction of
unfunctionalized 2,3-disubstituted phenyl acrylic acids and derivatives promoted by di-tert-butylper-
oxide gave above intermediates in high yields. The mild reaction conditions and easy purification
procedures of this method provide a new approach for the synthesis of phenanthrenes.
ß 2013 Cheng-Gang Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Received 6 July 2013
Received in revised form 4 October 2013
Accepted 23 October 2013
Available online 23 November 2013
Keywords:
Polymethoxylphenanthrene
Cross dehydrogenative coupling (cdc)
Radical cation
Intramolecular oxidative coupling
1. Introduction
for this CDC reaction, such as Pb(OAc)4, VOF3, VOCl3, FeCl3 [12]. The
application of these methods was restricted by tedious linear
The forming of C–C bonds is one of the most important tasks in
organic synthesis. The development of transition metal-catalyzed
coupling reactions greatly improves the efficiency of the building
of C–C bonds in recent decades [1]. However, some of the methods
need pre-functionalized materials [2]. Li proposed the concept of
Cross-dehydrogenative-coupling (CDC) reactions, which combine
two C–H bonds to form a new C–C bond, avoiding the need for
preparing pre-functionalized materials [3]. Then, Cu-catalysts [4],
Fe-catalysts [5], Pd-catalysts [6] and other metal catalysts for CDC
reactions were successively reported [7,8]. However, the develop-
ment of metal free CDC reactions has great significance in bulk
products and the production of fine chemicals [3].
procedures, low overall yields or difficult purification procedures.
Thus, it is necessary to find new metal free methods to broaden the
choices of building phenanthrenes
Herein, di-tert-butylperoxide (DTBP) was reported for the
intramolecular oxidative coupling reaction of unfunctionalized
2,3-diphenylacrylic acids and their derivatives at room tempera-
ture in trifluoroacetic acid (TFA)/CH3CN to give polysubstituted
phenanthrenes in good to excellent yields.
2. Experimental
All reactions were performed under air atmosphere unless
stated otherwise. DTBP was purchased from the Shanghai Taitan
Technology Co., Ltd. TFA was provided by Shanghai Darui Finechem
Ltd. All solvents, such as dichloromethane, acetonitrile and
toluene, were purchased from Kelong Chemical Reagent (Chengdu,
China) and were dried and purified by standard techniques before
use. 1H NMR and 13C NMR spectra were recorded using a Varian
Mercury Plus 400 and a Bruker Avance 600 spectrometer. HRMS
data were recorded on a BioTOFQ mass spectrometer (ESIMS). The
melting points were determined on an X-4 binocular microscope
melting point apparatus (Shanghai Precision Tech Instruments Co.,
Shanghai, China) and were uncorrected. The Supporting informa-
The phenanthrene ring is an important unit of tylophora
alkaloids. These alkaloids have polycyclic structures and several
bioactivities, especially antitumor activity, which aroused great
interest among chemists and pharmaceutical scientists [9,10]. The
key step of constructing such alkaloids and their analogs is the
preparation of polymethoxy-substituted phenanthrene [11].
Therefore, a simple and efficient method for such phenanthrenes
is noteworthy. Number of synthetic methods have been proposed
*
Corresponding author.
E-mail address: zcg93@aliyun.com (C.-G. Zhang).
1001-8417/$ – see front matter ß 2013 Cheng-Gang Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.11.004

D.-R. Ji et al. / Chinese Chemical Letters 25 (2014) 348–350
349
tion includes detail experimental procedures and the spectra data
of all substrates and products.
100.2, 55.9, 55.8, 52.1. IR (KBr, cmꢁ1):
n
2997, 2947, 2834, 1706,
1595, 1500, 1434, 1348, 1257, 1257, 1136, 1034; HRMS (ESI):
Calcd. for C19H16O6Na: m/z 363.0839 ([M+Na]+), found: 363.0841.
2,3,6,7-Tetramethoxyphenanthrene-9-carbonitrile (2e): Yield
85.1%. mp 266–268 8C [16]; 1H NMR (400 MHz, CDCl3):
2.1. General procedure for the preparation of 2,3-disubstituted phenyl
acrylic acid
d 7.99 (s,
1H), 7.73 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 4.15 (s, 3H),
4.14 (s, 3H), 4.08 (s, 3H), 4.05 (s, 3H).
A mixture of homoveratric acid, veratraldehyde, acetic anhy-
dride and triethylamine was stirred and heated at reflux for 24 h
under nitrogen atmosphere. The products were purified and
collected to give (E)-2,3-bis(3,4-dimethoxyphenyl)acrylic acid (1a)
and (Z)-2,3-bis(3,4-dimethoxyphenyl)acrylic acid (1b) [13,14]. By
following the same procedure as above (E)-2-(3,4-dimethoxyphe-
nyl)-3-(3,4-methylenedioxyphenyl)acrylic acid (1c) and (Z)-2-
(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylic ac-
id (1d) were obtained.
3. Results and discussion
(E)-Methyl 2,3-bis(3,4-dimethoxyphenyl)acrylate (1e) was
used as the substrate to investigate proper reaction conditions
for the desired coupling reaction. The results were summarized in
Table 1. To investigate the influence of DTBP, different quantities
were added and the desired product 2c was obtained in up to 68.8%
yield (Table 1, entries 1–5). Unreacted 1e existed after 1.5 h when
2.0 equiv. DTBP was added. However, when the reaction time was
prolonged to 4 h, the yield improved but 1e still did not react
completely (Table 1, entry 6). Further extension of the reaction
time to 8 h and 24 h did not improve the yield (Table 1, entries 7
and 8). Then, with 2.0 equiv. of DTBP and reaction time unchanged,
changing the dosage of TFA (1 mL, 2 mL, 3 mL, 5 mL, 10 mL), 3 mL
TFA brought a better yield of 72.8% (Table 1, entries 6, 9, 10, 11, 12).
Under the nitrogen atmosphere, the result was not improved
(Table 1, entry 13). Literatures reports suggested that CH2Cl2 was
frequently used in the CDC reactions such as the transformation of
1e–2c [12]. For this method, however, TFA was more suitable than
CH2Cl2 (Table 1, entries 8, 14).
2.2. General procedure for the preparation of methyl 2,3-disubstituted
phenylacrylate
Esterification of 1a in methanol and sulfuric acid in the usual
manner followed by a recrystallization from ethyl acetate afforded
the pure methyl (E)-2,3-bis(3,4-dimethoxyphenyl)acrylate (1e) as
a
white solid. Using the same procedures, (Z)-2,3-bis(3,4-
dimethoxyphenyl)acrylate (1f), methyl (E)-2-(3,4-dimethoxyphe-
nyl)-3-(3,4-methylenedioxyphenyl)acrylate (1g), methyl (Z)-2-
(3,4-dimethoxyphenyl)-3-(3,4-methylenedioxyphenyl)acrylate
(1h) were also obtained [15].
2.3. Preparation of (Z)-2,3-bis(3,4-dimethoxyphenyl)acrylonitrile
(1i)
Table 1
A mixture of cyanide, veratraldehyde, ethanol, and sodium
ethoxide was stirred and heated to reflux for 2 h. The product was
collected and dried to give 1i as a yellow solid [16].
Optimization of the intramolecular coupling reaction.a
OMe
OMe
MeO
MeO
MeO
2.4. General procedures for the oxidative coupling reaction
COOMe
COOMe
DTBP
solvent, r.t.
To a solution of 1e (0.2 mmol, 71.6 mg) in acetonitrile (2 mL)
was added DTBP (0.2 mmol ꢀ 2 mmol, 58.4 mg) and CF3COOH
(4 mL). The mixture was stirred and the reaction tube was sealed at
room temperature for 4 h and then quenched by water (10 mL).
The aqueous phase was extracted with dichloromethane
(3 mL ꢀ 10 mL). The combined organic extracts were dried over
with MgSO4, filtered, concentrated using a rotary evaporator and
purified by chromatographic column to give the desired product 2c
as a light yellow solid. Coupling reactions of the other substrates
followed the same procedure.
Methyl 2,3,6,7-tetramethoxyphenanthrene-9-carboxylate (2c):
Yield 88.5%. mp 203–204 8C [15]; 1H NMR (400 MHz, CDCl3):
d 8.65
(s, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.26 (s, 1H), 4.14 (s,
3H), 4.13 (s, 3H), 4.08 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H).
2,3,6,7-Tetramethoxyphenanthrene-9-carboxylic acid (2a):
Yield 91.4%. mp 283–285 8C [13]; 1H NMR (400 MHz, DMSO):
MeO
1e
2c
OMe
OMe
Entry
DTBP (equiv.)
Solvent (mL)
Time (h)
Yieldb (%)
1
2
1.1
1.3
1.5
2.0
2.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0
TFA (3)
6.5
6.5
1.5
1.5
1.5
4
Trace
24.1
65.4
68.8
67.6
72.8
65.2
60.7
61.2
68.4
68.3
48.9
67.6
ND
TFA (3)
3
TFA (3)
4
TFA (3)
5
TFA (3)
6
TFA (3)
7
TFA (3)
8
8
TFA (3)
24
9
TFA (1)
4
4
4
4
4
4
4
4
4
4
4
4
4
4
10
11
12
13c
14
15
16
17
18
19
20
21d
22d
TFA (2)
TFA (5)
d
TFA (10)
12.86 (brs, 1H, –COOH), 8.55 (s, 1H), 8.42 (s, 1H, H-30), 8.05 (s, 1H),
8.01 (s, 1H), 7.56 (s, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.92 (s, 3H), 3.89
(s, 3H).
2,3-Methylenedioxy-6,7-dimethoxyphenanthrene-9-carboxyl-
ate acid (2b): Yield 86.4%. mp 265–266 8C [14]; 1H NMR (400 MHz,
TFA (3)
DCM (3)
CH3CN (3)
Toluene (3)
TFA/DCM (2/1)
TFA/DCM (1/1)
TFA/CH3CN (2/1)
TFA/CH3CN (1/1)
TFA/CH3CN (2/1)
TFA/CH3CN (2/1)
ND
ND
21.6
18
88.5
75.6
84.0
ND
CDCl3): d 8.60 (s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.22 (s,
1H), 6.12 (s, 2H), 4.09 (s, 3H), 4.07 (s, 3H), 4.01 (s, 3H).
Methyl 2,3-methylenedioxy-6,7-dimethoxyphenanthrene-9-
carboxylic (2d): Yield 92.3%. mp. 210–213 8C; 1H NMR
a
Reaction conditions: 1e (0.1 mmol), DTBP (0–2.5 equiv.) in 1–10mL of solvent
(400 MHz, CDCl3):
(s, 1H), 7.22 (s, 1H), 6.12 (s, 2H), 4.09 (s, 3H), 4.07 (s, 3H), 4.01 (s,
3H). 13C NMR (100 MHz, CDCl3):
168.1, 149.9, 149.2, 148.9, 147.1,
130.5, 128.7, 125.6, 125.4, 124.1, 122.1, 106.5, 106.4, 102.5, 101.5,
d 8.60 (s, 1H), 8.34 (s, 1H), 7.80 (s, 1H), 7.73
was stirred at room temperature for 4 h.
b
Isolated yield.
c
d
At nitrogen atmosphere.
d
At oxygen atmosphere.

350
D.-R. Ji et al. / Chinese Chemical Letters 25 (2014) 348–350
Table 2
Substrate scope of intramolecular oxidative coupling with DTBP as sole oxidant.a
Appendix A. Supplementary data
OMe
OMe
MeO
MeO
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.
11.004.
R
3
R
DTBP (2 equiv.)
CF COOH, CH CN, r.t.
3
3
3
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R
R
1
1
1
2
R
R
2
2
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Acknowledgments
The authors are grateful to Sichuan Provincial Education
Department (No. 12ZA141) and Key Laboratory of Advanced
Functional Materials of Sichuan Province Higher Education System
(No. KFKT2013-01) and Sichuan Normal University (No. XYZ2013-
14-37) for financial support.